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Antibody-Mediated Rejection in Kidney Transplantation

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Antibody-Mediated Rejection in Kidney Transplantation FDA Public Workshop: Antibody-mediated Rejection in Kidney Transplantation The Choice of Induction / Maintenance Immunosuppression and their Impact on Preexisting and De Novo Antibodies Millie Samaniego, MD, FACP, FASN, FAST Alan B. Leichtman Collegiate Chair of Transplant Nephrology Professor of Medicine University of Michigan Disclosures • I have nothing to disclose in relation to this presentation: • Following drugs used “off label” will be discussed: • Thymoglobulin • Campath • IVIg • Belatacept • Rituximab • Eculizumab • C1q Inhibitors TABLE 1 The Treatment of Acute Antibody-Mediated Rejection in Kidney Transplant Recipients-A Systematic Review. Roberts, Darren; Jiang, Simon; Chadban, Steven Transplantation. 94(8):775-783, October 27, 2012. DOI: 10.1097/TP.0b013e31825d1587 TABLE 1 Therapeutic agents used against DSAs in the treatment of antibody- mediated rejection and the evidence supporting their role © 2012 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2 FIGURE 2 The Treatment of Acute Antibody-Mediated Rejection in Kidney Transplant Recipients-A Systematic Review. Roberts, Darren; Jiang, Simon; Chadban, Steven Transplantation. 94(8):775-783, October 27, 2012. DOI: 10.1097/TP.0b013e31825d1587 FIGURE 2 . Trends in the use of treatments for AMR over time on the basis of all publications identified in the systematic review. Using a gray scale, black represents the most commonly used (in the case of PP, approximately 700 patients were treated between 2007 and 2011), whereas no color (white) means that it was not used. This includes patients from any observational, treatment, or epidemiology-based study identified in the systematic review. The use of tacrolimus and mycophenolate in patients with AMR is likely to be underrepresented in this figure because in recent years, these treatments are commonly used as baseline immunosuppression for high-risk KTRs, whereas the data included here only included new treatments administered to patients in response to a diagnosis of AMR/vascular rejection. © 2012 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 4 ABMR Protocols • Suppression of the T-cell response • Elimination of pre -formed antibody • Inhibition of residual antibody and the complement system cascade • IVIg • Eculizumab • C1q inhibitors • Depletion of antibody producing cells and/or their precursors • Rituximab ABMR Protocols •Suppression of the T -cell response • Depletional Agents • Polyclonal: rATG • Humanized antibodies: Alemtuzumab • Non-depletional Agents • Belatacept Tra n sp lantati on 9 7 ( 6) March 20 14 Methods • 114 moderately sensitized deceased donor renal transplant recipients between December 2009 and November 2011 • Positive DSA (MFI max 500-4,000 by SAB Luminex) • Negative flow crossmatch • Induction: ATG or basiliximab based on provider preference • Maintenance: TAC/MPA/Pred • Followed for 36 months • De novo DSA • Defined as the absence of pre-transplant DSA (MFI less than 300) increasing at least three -fold (greater than 900 MFI) post-transplant • Assessed blindly by HLA lab director (TE) Summary and Conclusion • Induction with ATG (thymoglobulin) is associated with a reduction in the incidence of dnDSA and ABMR without a significant change in the incidence of CMV infection or BK nephropathy when compared with basiliximab in moderately sensitized deceased donor renal transplant recipients • Randomized clinical trials are required to specifically address the role of induction immunosuppression on dnDSA and ABMR ALEMTUZUMAB (CAMPATH-1H) • A recombinant DNA- derived humanized monoclonal antibody directed against CD52 • IgG1 kappa with human variable framework and constant regions with murine CDR regions Uses of Alemtuzumab in Kidney Transplantation • Antibody-Induction Agent: • CNI avoidance • Steroid-free protocols • CNI monotherapy • “Prope” tolerance induction • Induction of HIV patients undergoing KTx • Induction in desensitization protocols • Treatment of Acute Rejection: • Four studies encompassing an N=62 • Two studies used Campath -1H and one Campath-1G • Two published in a peer-reviewed journal De Novo a-HLA Antibodies in Alemtuzumab Induction • Cai J et al: Transplantation 2004; 78:919 -924 • 42% (n=10) of the patients enrolled in the pilot study of alemtuzumab induction for CNI avoidance have developed Class I and Class II a -HLA antibodies • 60% DSA • 40% non-DSA • At 24 mos of F/U: • Of 10 Pts developinG a-HLA antibodies, 4 (40%) have had BPAMR • Of these: • 3 patients had DSA a-HLA antibodies • 1 patient had non-DSA a-HLA antibodies Alemtuzumab Induction in Renal Transplantation Michael J. Hanaway, M.D., E. Steve Woodle, M.D., Shamkant Mulgaonkar, M.D., V. Ram Peddi, M.D., Dixon B. Kaufman, M.D., Ph.D., M. Roy First, M.D., Richard Croy, M.A., John Holman, M.D., for the INTAC Study Group N Engl J Med Volume 364(20):1909-1919 May 19, 2011 J Am Soc Nephrol 28: 2017 Rituximab+IVIg: Final Verdict? • 2/11-6/12: • Randomized to IVIg+Placebo or IVIg+Ritux • Total enrollment goal = 90 patients • End-points: • Rates of Transplantation • ABMR • Protocol biopsies at 1 year • Scr, DSA monitoring • Patient and Graft survival Transplantation. 98(3):312-319, August 15, 2014. DOI: 10.1097/TP.0000000000000064 FIGURE 1 Benefits of Rituximab Combined With Intravenous ImmunoGlobulin for Desensitization in Kidney Transplant Recipients. Vo, Ashley; Choi, Jua ; Cisneros, Kristen; Reinsmoen, Nancy; Haas, Mark; Ge, Shili ; Toyoda, Mieko; Kahwaji, Joseph; Peng, Alice; Villicana, Rafael; Jordan, Stanley Transplantation. 98(3):312-319, August 15, 2014. DOI: 10.1097/TP.0000000000000064 FIGURE 1 . Study design. Patients were randomized in a 1:1 ratio to receive IVIG+placebo versus IVIG+rituximab. Treatment is as described in the text. The attribution to study groups is shown. Briefly, 15 patients were enrolled. Of those, 87% underwent transplantation. Seven patients were randomized to IVIG+placebo group; six patients were randomized to IVIG+rituximab group. Outcomes are described in the text. © 2014 by Lippincott Williams & Wilkins. Published by LippincottTransplantation. Williams & Wilkins, Inc. 98(3):312-319, August2 15, 2014. DOI: 10.1097/TP.0000000000000064 Outcomes End-points Blinded study IVIg IVIg+Ritux Enrollment 15 Transplant 11 (73%) 5 6 Rate ABMR 3 3 (43%) 0 Graft loss 2 2 0 Cause of GL ABMR, BKVN 0 Rx of ABMR required PLEX+Ritux+Eculizumab Efficacy similar in enabling transplantation by reduction of DSA DSA monitoring showed rebound at 6 mo in the IVIg placebo group associated with 60% severe AMBR (3/6) IVIg+Ritux patients (50%; 3/6) had no ABMR in protocol Bx clinical investigation AM Jackson et al.: Rituximab induction and HLA antibody production transplantation using a desensitization protocol that transplant. In patients transplanted without rituximab, more either did or did not include a single dose of rituximab HLA antibodies were increased at 1 month post transplant, (375 mg/m2) the day before transplantation. Patient demo- 32% (eight of 25) of DSAs and 55% (50 of 91) of non-DSAs. graphics are provided in Table 1 and reflect our practice of The frequency of HLA antibody rebound was significantly using rituximab for patients with a higher risk for AMR.27,28 higher in patients transplanted without rituximab induction The 25 patients who received rituximab induction had for both DSA, P 0.03, and non-DSA, P 0.003. Moreover, broader sensitization (mean calculated panel reactive anti- the magnitude of¼ the antibody increase¼ was also larger in body (CPRA) 80 vs. 60%, P 0.02), a higher incidence of patients transplanted without rituximab induction. The previous transplants¼ (76 vs.¼ 28%, P 0.002), and repeat mean percentage increase at 1 month for all HLA antibodies ¼ HLA mismatches (80 vs. 0%, Po0.0001). However, the two examined was 294 (median 70) among the lower immu- cohorts had similar DSA levels before desensitization and nologic risk patients transplanted¼ without rituximab, com- received a similar number of plasmapheresis treatments pared with 207 (median 10) for those transplanted with (Table 1, P 0.20). rituximab induction (P ¼0.02). HLA antibody¼ monitoring within the first 2 weeks post In both cohorts, HLA¼ antibody rebounds detected at transplant revealed an increase in DSA for 36% (nine of 25) 1–3 months post transplant were transient, with 95 of 105 of rituximab-treated patients and 44% (11 of 25) of non- antibodies (90%) subsiding without any further plasmaphe- treated patients transplanted without rituximab (P 0.77). resis treatments. Of the 10 DSAs detected at 1 month post Elevated DSA was treated with continued plasmapheresis¼ and transplant, seven remained at a low level detectable only by low-dose intravenous immunoglobulin (IVIg); however, all bead immunoassays. The remaining three DSAs were of patients completed desensitization treatments within 2 weeks moderate levels, detected at a level sufficient to yield a weakly of transplant. An extended analysis was performed on 256 positive FCXM. These stronger rebounds occurred in three HLA antibodies (DSA and non-DSA) to examine HLA patients, two of whom received rituximab induction. antibody levels following the cessation of plasmapheresis/ Protocol biopsy surveillance at 1 month identified subclinical IVIg treatments. The percentage change, comparing HLA rejection (histopathology evidence of AMR without graft antibody levels before desensitization (time zero) with four dysfunction) in seven patients with DSA rebound, including time points (1, 3, 6, and 12
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